Aerosol composition



United States Patent 3,155,574 AEROSOL COMPOSITION John E. Siison,Pleasantville, and John Frangos, Brooklyn,

N.Y., assignors to Revlon, Inc., New York, N.Y., a corporation ofDelaware No Drawing. Filed May 24, 1962, Ser. No. 197,284 11 Claims.(Cl. 167-54) This invention relates to aerosol compositions, and tomethods for making and using the same. In particular, this inventionrelates to aerosol compositions containing nitroglycerin, to methods ofmaking the same, and to the use of such aerosol compositions ininhalation therapy.

The beneficial effects of nitroglycerin in relieving the pain associatedwith angina pectoris has long been known in the art. Although numerousother medicaments have been prescribed for the treatment of anginalpain, nitroglycerin remains the most effective and medically safest-therapeutic agent in this field.

The clinical role, administration, and effects of nitroglycerin andother anti-anginal drugs are extensively discussed in recent articles byModell in Clinical Pharmacology and Therapeutics, pp. 97-198 (1962), andby Russek et al. in Postgraduate Medicine, pp. l50155 (February 1962).As emphasized in these articles, the only clinically useful means ofadministering nitroglycerin heretofore have been sublingually andparenterally. Nitroglycerin is relatively involatile, and not suitableto administration by direct inhalation of its fumes. Further, of course,the explosive properties of nitroglycerin have heretofore required thatit be combined with a solid desensitizing agent (e.g., a therapeuticallyinert substance such as mannitol) in the form of tablets.

As pointed out in the article by Modell, the oral administration ofnitroglycerin is of little value because the time required for the drugto be absorbed into the blood stream and carried to the coronaryarterioles usually far exceeds the duration of the paroxysm of anginalpain which the drug is intended to relieve, and the drug is rapidlydestroyed in the gastro-intestinal tract or is removed by the liver.

Sublingual administration suffers from similar limitations. The speed ofaction of sublingual administration may be as long as 2 to 3 minutes.Further, sublingual administration is erratic, since there is no controlover the amount of nitroglycerin eiiectively absorbed by the mucousmembranes of the mouth. Further, the nitroglycerin present in theuncoated tablets of the prior art is gradually decomposed on exposure toair and the efiicacy of the tablets is reduced with time. This lack ofstability of the tablets is not only undesirable from a marketingstandpoint, but also contributes to the problem of erratic dosing.

The present invention concerns methods for treating anginal painassociated with constriction of the coronary arteries with nitroglycerinby inhalation therapy, specifically by inhalation of anitroglycerin-containing aerosol composition. According to the methodsof the invention, safe, controlled, and speedy administration ofnitroglycerin can be effected. Inhalation therapy, with pulmonaryabsorption of nitroglycerin into the bloodstream, is comparable in speedto intravenous administration, and insures prompt delivery of thenitroglycerin to the coronary arterioles in about 30 seconds or so. Theuse of metered valves with aerosol packages of the compositions of theinvention insures that a controlled dose of the drug is administred.Since, in the aerosol package, the nitroglycerin is not exposed to thedeleterious influences of air, the compositions retain their potency andefiicacy at original levels, making the product not only more accuratefor dosing purposes, but more desirable from a marketing viewpoint.

The compositions of the present invention comprise 3,155,574 PatentedNov. 3, 1964 from about 30 to about percent by weight of a nontoxicvolatile liquefied and/or liquid propellant, preferably from about 65 toabout 95 percent, in admixture with about 5 to about 50 percent,preferably about 5 to about 25 percent, by Weight of a non-toxicsubstance solubilizing a desensitized nitroglycerin component in thepropellant, the balance being a stabilized nitroglycerin component inwhich component about 1 to about 10 percent by weight, preferably about5 to 10 percent, is the therapeutically active nitroglycerin and thebalance is a nontoxic non-volatile liquid desensitizing agent for thenitroglycerin.

Suitable non-toxic volatile liquid or liquefied propellants are Wellknown in the aerosol art. These materials are generally fluorinated,chlorinated, or fiuorochlorinated saturated lower aliphatichydrocarbons, or liquefied petroleurn gases. Suitably halogenated loweralkanes containing 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms,and at least 1 fluorine atom, are often generically referred to asfiuorohydrocarbon propellants, and are commercially available under thetrade names Freons, Genetrons, Ucons, etc. These materials include suchparticularly useful propellants as dichlorodifluoromethane (Freon 12),dichlorotetrafiuoroethane (Freon 114),

trichloromonofluoromethane (Freon l1), and octafluo-' rocyclobutane(Freon C3 18). Other examples of suitable propellants are ethylchloride, 1,1,l-trichloroethane, butane, isobutane, propane, etc.

The propellants, or suitable mixtures thereof (which mixtures are alsoreferred to herein simply as propellants) are such as produce adesirable vapor pressure for the composition between about 15 and about60 pounds per square inch at room temperatures (20-25 0.), preferablybetween about 35 and about 40 pounds per square inch at thesetemperatures. A combination of propellants particularly suitable for usein the present invention comprises a mixture of about 60 parts by Weightof Freon 12 with 40 parts by weight of Freon 11. However, it is to beunderstood that individual Freons or mixtures of Freons can be employedin the invention in various amounts with the other ingredients mentionedbefore so that the resulting mixtures show a pressure within the limitsrecited.

As the non-toxic agent solubilizing the stabilized nitroglycerincomponent, in the propellants just mentioned, ethyl alcohol has provedto be particularly suitable. This substance promotes the formation ofuniform, homogeneous mixtures of the nitroglycerin-containing componentwith the propellants, and is unobjectionable from a clinical standpoint.The alcohol is suitably employed in amounts sufiicient to preventseparation of the nitroglycerin from the propellant but insufficient toreduce the volatility of the final composition below the pressure limitsmentioned earlier as desirable in areosol packages.

The nitroglycerin-containing component, which is a mixture ofnitroglycerin with one or more non-toxic nonvolatile liquiddesensitizing agents, is compounded to contain from 5 to 10 percent byweight of nitroglycerin. If the amount of nitroglycerin is much inexcess of the latter figure, the sensitivity of the composition mayincrease to a point at which the highly safe properties of the presentcompositions are lost. On the other hand, decreasing the amount ofnitroglycerin in the composition merely increases the amount oftherapeutically inactive desensitizing agent administered.

The desensitizing agents are preferably those non-toxic non-volatileliquid compounds having at least 3 carbon atoms and characterized by thestructural formula XO(RO),,Y, in which R is alkylene, ketoalkylene orhydroxyalkylene having from 2 to 6 carbon atoms, X and Y may bedifferent and are alkyl, ketoalkyl, hydroxyalkyl,

acyl, oxy-substituted acyl, and hydrogen, and n is an integer from 1 to10. Exemplary of desensitizing substances of this class are thefollowing: propanediol-1,2; diethylene glycol; polypropylene glycol(M.W. 400); diethylene glycol diacetate; polyethylene glycol (M.W. 200);diethyleneglycol butyl ether; glycol monoethyl ether; diethyleneglycoldiethyl ether; diacetone alcohol; triethylene glycol; polyethyleneglycol (M.W. 300); hydroxyethyl acetate; diethyleneglycol ethyl ether;dimethoxytetraglycol; trimethylene glycol; glycol diethyl ether;ethoxyethyl acetoxyethyl ether; diethyleneglycol methyl ether;methoxyethyl acetoxyethyl ether; glycol monomethyl ether; bis-(methoxyethyl) formal; bis(methoxyethyl) acetal; 2-methoxymethyl-2,4-dimethylpentane diol-1,5; butanedioi- 1,3;Z-methyl-pentanediol-2,4, and the like.

Of these materials, propanediol-1,2 has proved particularly suitable foruse in the compositions of the invention, not only because of itsexcellent desensitizing properties, but also because of its extremelylow toxicity. The glycol is compatible with the propellants commonlyused in aerosol compositions, and blends well with the remainingcomponents of the aerosol compositions of the invention with theformation of a homogeneous solution.

However, other of the sensitizing agents described above, particularlyother glycols, can be used in compounding the compositions of theinvention. Because of the extremely small amounts of sensitizing agentdispensed in practicing the inhalation therapy of nitroglycerinaccording to certain methods of the present invention, toxicity problemsare minimized, and many materials otherwise considered unsuitable forinhalation can be employed. Thus, in administration of a dose ofnitroglycerin of between about 0.05 to about 1.0 milligram, preferably0.1 to 0.4 milligram, as contemplated by the present invention, aslittle as about 0.45 milligram of the desensitizing agent is inhaled.

In referring to the desensitizing agents, the term nonvolatile, as usedherein, is defined as having vapor pressure characteristics such thatevaporation of a mixture of nitroglycerin and the desensitizer in theproportions contemplated herein will not leave a nitroglycerin residue,e.g., the desensitizer has vapor pressure characteristics similar tothose of nitroglycerin. The use of such a desensitizing agent insuresthat if, by accident, an aerosol container containing the compositionsof the invention is punctured, with loss of the propellants, and,perhaps, the alcohol component, any residue will still be a desensitizednitroglycerin mixture, the desensitizer being the least fugitiveingredient of the composition, persisting even in the preference to thenitroglycerin under volatilizing conditions.

The compositions of the invention are conveniently prepared bydissolving a pharmaceutical grade of nitroglycerin in a suitable liquiddesensitizer. This combination is then mixed with a solubilizing agentsuch as absolute ethyl alcohol. This mixture may then be combined withthe propellants and put into containers, or the mixture and propellantsmay be separately put into containers by conventional cold fill orpressure methods.

The products of the invention are conveniently used in aerosolcontainers having a metered valve which dispenses a controlled quantityof the self-propelling aerosol composition as a single dose. Thesecontainers are Well known in the art, and may be made of any materials,such as glass, plastic, or metal adequate to contain the pressuresgenerated by the volatile propellant materials therein. Conventionally,these metered containers operate by filling a well of predeterminedvolume with the self-propelling composition which is dispersed as anareosol.

When used in such a metered valve container, the amounts of propellantand active ingredients in the aerosol composition and the quantity ofcomposition delivered by the valve are, relatively, such that a desiredpredetermined dose of active ingredient is delivered.

Administration is suitably effected by directing the orifice of theaerosol unit into the mouth and simultaneously inhaling and activatingthe metered valve.

A better understanding of the invention and of its many advantages willbe had by referring to the following examples, given by way ofillustration.

Example 1 An aerosol composition suitable for inhalation therapy andhaving a pressure of 53 p.s.i.g. at 70 F. was prepared by combining 4weight percent of a combination of propanediol-l,2 and nitroglycerincontaining 10 weight percent of nitroglycerin with 10 parts by weight ofanhydrous ethyl alcohol, 51.6 parts by weight of dichlorodifluoromethane(Propellant 12), and 34.4 parts of dichloromonofluoromethane (Propellant11).

Butanediol-LZ, propanediol-L3 or polypropylene glycol (MFN. about 300)can be substituted for propanediol-1,2 as desensitizers.

Example 2 A composition having a vapor pressure of 45 p.s.i.g. wasprepared from 1.43 parts by Weight of a mixture containing 10 percentnitroglycerin (N6) in propanediol- 1,2 (PG), 10 parts of anhydrousethanol, 53.13 parts of ropellant 12, and 35.44 parts of Propellant 11.

Example3 10% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant 12 26.0Propellant 11 39.0

Pressure: 36 p.s.i.g.

Example4 5% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant l2 39.0Propellant 11 26.0

Pressure: 43 p.s.i.g.

ExampleS 10% NG/PG 20.0 Anhydrous ethanol 25.0 Propellant 12 33.0Propellant 11 22.0

Pressure: 45 p.s.i.g.

Example6 10% NG/PG 10.0 Anhydrous ethanol 35.0 Propellant 12 20.0 Ethylchloride 35.0

Pressure: 25 p.s.i.g.

Example7 10% NG/PG 10.0 Anhydrous ethanol 40.0 Propellant 11 30.0Isobutane 20.0

Pressure: 21 p.s.i.g.

Example8 10% NG/PG 10.0 Anhydrous ethanol 50.0 Propellant 12 30.01,1,1-trichloroethane 10.0

Pressure: 36 p.s.i.g.

Example9 10% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant l2 8.0Propellant 11 32.0 Dichlorotctrafluoroethane (Propellant 114) 25.0

Pressure: 22 p.s.i.g.

Example 10% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant 12 50.7Propellant 114 14.3

Pressure: 55 p.s.i.g.

Example 11 10% NG/PG 10.0 Anhydrous ethanol 25.0 1,1-difluoroethane 65.0

Pressure: 60 p.s.i.g.

Example 12 10% NG/PG 10.0 Anhydrous ethanol 25.0l-chloro-l,l-difluoroethane 65.0

Pressure: p.s.i.g.

Atlhough specific embodiments have been described in the examples, andalthough various preferences, recommendations, and alternatives havebeen given, it is to be understood that these are not exhaustive orlimiting of the invention, but are illustrative and for the purpose ofinstructing others in the principles of the invention and how to modifyit so that they may be able to use it in a variety of embodiments asbest suited to the conditions and requirements of a particular use.

What is claimed is:

1. An aerosol composition comprising a liquefied propellant,nitroglycerin and a non-volatile liquid desensitizing agent therefor,and an agent solubiiizing said nitroglycerin in said propellant.

2. An aerosol composition comprising a liquefied propellant, ethylalcohol, nitroglycerin and a non-volatile liquid desensitizing agenttherefor of the formula in which R is selected from the group consistingof alkylene, ketoalkylene, and hydroxyalkylene having 2-6 carbon atoms,X and Y are individually selected from the group consisting of alkyl,ketoalkyl, hydroxyalkyl, acyl, oxy-substitutcd acyl, and hydrogen, and nis an integer from 1 to 10.

3. A composition as in claim 2 wherein said desensitizing agent is aglycol.

4. A desensitized nitroglycerin-containing areosol compositioncomprising about 30-95 percent by weight of a volatile non-toxicliquefied propellant, about 5-50 percent by weight of ethyl alcohol, thebalance being a mixture containing about 1-10 percent by weight ofnitroglycerin with a non-toxic non-volatile liquid glycol.

5. A composition as in claim 4 wherein said glycol is propanediol-LZ.

6. The method of treating anginal pain by inhalation therapy whichcomprises inhaling between about 0.05-1.0 milligram of nitroglycerin inan aerosol composition containing the same, said composition comprisinga volatile non-toxic liquefied propellant, ethyl alcohol, andnitroglycerin, and a non-toxic non-volatile liquid desensitizing agenttherefor.

7. The method as in claim 6 wherein said non-toxic liquefied propellantis selected from the group consisting of fluorinated andfluorochlorinated saturated lower aliphatic hydrocarbons and saiddesensitizing agent is a glycol.

8. The method of treating anginal pain which comprises inhaling between0.05-1.0 milligram of nitroglycerin in an aerosol composition containingthe same, said composition comprising about 30-95 percent by weight of avolatile non-toxic liquefied propellant selected from the groupconsisting of liquefied petroleum gases, chlorinated, fluorinated andfluorochlorinated saturated lower aliphatic hydrocarbons, about 5-50percent by weight of ethyl alcohol, the balance being a mixturecontaining about 1-10 percent by weight of nitroglycerin with anon-toxic non-volatile glycol.

9. The method as in claim 8 wherein said glycol is propanediol-1,2.

10. The method as in claim 8 wherein said composition has a vaporpressure of about 15-60 pounds per square inch at room temperatures andsaid propellant is at least one fluorochlorinated saturated loweraliphatic hydrocarbon.

11. The method as in claim 10 wherein said glycol is propanediol-1,2.

References Cited in the tile of this patent UNITED STATES PATENTS2,648,698 Preckel Aug. 11, 1953 2,868,691 Porush et al. Jan. 13, 19593,014,844 Thiel et al. Dec. 26, 1961 OTHER REFERENCES Russek et al.:Paradoxical Action of Glyceryl Trinitrate (Nitroglycerin) in CoronaryPatents, J. Am. Med. Assoc., volume 158, No. 12, pages 1017-1021, July23, 1955.

Riseman: Current Concepts in Therapy, the Treatment of Angina Pectoris(HI); I. New England 1. Medicine, volume 261, No. 20, pages 1017-1020,November 12, 1959; II. Ibid., volume 261, No. 22, pages 1126-1129,November 26, 1959.

1. AN AEROSOL COMPOSITION COMPRISING A LIQUEFIED PROPELLANTNITROGLYCERIN AND A NON-VOLATILE LIQUID DESENSITZING AGENT THEREFOR, ANDAN AGENT SOLUBILZING SAID NITROGLYCERIN IN SAID PROPELLANT.